Method for absorption of drugs

ABSTRACT

A method for enhancing drug or antibiotic blood levels by inducing gastrointestinal hypomotility and resultant delayed gastrointestinal transport thus increasing dwell time in the upper portion of the gastrointestinal tract where many drugs, particularly antibiotics, are preferentially absorbed. The method involves orally administering, simultaneously or sequentially, a drug, such as an antibiotic, and about 10-95 percent by weight of a non-anticholinergic antispasmodic agent, which is not absorbed and which has no systemic activity. Preferably, the administration is accomplished by orally administering a composition comprising the drug and the polymer simultaneously in conventional oral dosage form, preferably in a soft gelatin capsule. The agent is a polyoxypropylene-polyoxyethylene block polymer having the formula:   WHEREIN B REPRESENTS A MOLECULAR WEIGHT OF AT LEAST 900 AND A AND C REPRESENT A MOLECULAR WEIGHT OF ABOUT 5 - 80 PERCENT OF THE TOTAL MOLECULAR WEIGHT OF THE POLYMER.   D R A W I N G

United States Patent [191 Miskel et [4 1 Feb. 18, 1975 METHOD FORABSORPTION OF DRUGS [73] Assignee:

[22] Filed:

R. P. Scherer C0rp., Detroit, Mich.

Feb. 7, 1972 [21] Appl. No.: 224,300

Related U.S. Application Data [63] Continuation-impart of Ser. No.67,276, Aug. 26, 1970, abandoned, which is a continuation-in-part ofScr. No. 3,188, Jan. 15, 1970, abandoned.

[52] U.S. Cl 424/37, 424/4, 424/9, 424/78 [51] Int. Cl A6lj 3/07, A6lj3/10, A6lk 9/04 [58] Field of Search 424/37, 78

[56] References Cited UNITED STATES PATENTS 2,889,252 6/1959 Valentineet a1. 206/84 2,938,832 5/1960 Huggins et a1. 424/313 2,953,496 9/1960Phillips 424/358 X 3,140,232 7/1964 Noseworthy 424/227 3,150,043 9/1964Lafon 424/19 3,202,578 8/1965 Parker 424/78 3,248,289 4/1966 Shinozakiet a1. 424/278 X 3,308,217 3/1967 Lowy et a1 264/117 3,401,218 9/1968Misher 424/78 3,465,083 9/1969 Bartley et a1. 424/342 FOREIGN PATENTS ORAPPLICATlONS 1,051,240 12/1966 Great Britain 763,930 7/1967 Canada GreatBritain France Primary ExaminerShep K. Rose Attorney, Agent, orFirmMolinare, Allegretti. Newitt & Witcoff [57] ABSTRACT A method forenhancing drug or antibiotic blood levels by inducing gastrointestinalhypomotility and resultant delayed gastrointestinal transport thusincreasing dwell time in the upper portion of the gastrointestinal tractwhere many drugs, particularly antibiotics, are preferentially absorbed.The method involves orally administering, simultaneously orsequentially, a drug, such as an antibiotic, and about 10-95 percent byweight of a non-anticholinergic antispasmodic agent, which is notabsorbed and which has no systemic activity. Preferably, theadministration is accomplished by orally administering a compositioncomprising the drug and the polymer simultaneously in conventional oraldosage form, preferably in a soft gelatin capsule. The agent is ap0lyoxypropylene-polyoxyethylene block polymer having the formula:

C -CH C -CH -O -H HO(CH CHz O) H z O) H2 2 )c CH3 wherein b represents amolecular weight of at least 900 and a and c represent a molecularweight of about 5 80 percent of the total molecular weight of thepolymer.

6 Claims, N0 Drawings METHOD FOR ABSORPTION OF DRUGS REFERENCE TORELATED CASES This is a continuation-in-part of our co-pendingapplication Ser. No. 67,276, filed Aug. 26, 1970 now abandoned, which isa continuation-in-part of U.S. Patent Application Ser. No. 3188, filedJan. 15, 1970, now abandoned.

BACKGROUND OF THE INVENTION, FIELD OF THE INVENTION AND DESCRIPTION OFTHE PRIOR ART This invention relates a method for enhancing drug bloodlevels, particularly those of antibiotics, by inducing gastrointestinalhypomotility and resultant delayed gastrointestinal transport, therebyincreasing dwell time of the drug in the upper portion of thegastrointestinal tract, where the drug is preferentially absorbed.

The invention is most advantageously used in enhancing the blood levelsof antibiotics. Among the antibiotics are included the tetracyclines,griseofulvin and chloramphenicol. According to Goodman and Gilman, ThePharmacological Basis of Therapeutics, page 1,246, the tetracyclines areadequately but incompletely absorbed from the gastrointestinal tract.Absorption is most active in the stomach and upper small intestine, andit is much less effective in the lower portion of the intestinal tractand is negligible from the colon. After a single oral dose, the peakplasma levels of the tetracyclines are attained in 2 to 4 hours, andpersist for 6 hours or longer. A 6 hour interval between doses isnormally recommended. The administration of 250 mgs. every 6 hoursproduces plasma concentrations of 1-3 micrograms per ml. after thesecond dose, and these levels are maintained during continued treatment.

Also, according to Goodman and Gilman, page 1,297, the oraladministration of griseofulvin produces peak plasma concentrations inabout four hours. There is a considerable variation and fluctuation inplasma drug level in the same subject given equal quantities. This isbelieved to be due to difficulty in absorption from the intestine,primarily the upper small intestine, because of the insolubility ofgriseofulvin in an aqueous media.

As to chloramphenicol, Goodmand and Gilman, page l,26l, state that it israpidly absorbed from the gastrointestinal tract. Significant plasmalevels are obtained within 30 minutes and peak concentration is reachedin about 2 hours.

In addition to the antibiotics, drugs generally are preferentiallyabsorbed in the upper gastrointestinal tract. Thus, although the presentinvention may find its most important application in treatment withantibiotics, the inventive method may advantageously be used intreatment with a wide variety of drugs. Among the drugs are included thecorticosteriods, steroidal hormones, synthetic estrogens, thiazidediuretics, carbamate tranquilizers, phenothiazine tranquilizers, naturaland synthetic anti-hypertensives, nitrate ester cardiac vasodilators,coumarin derived anticoagulants, barbiturates, sulfa drugs, digitalisglycosides, sulfonylurea hypoglycemic agents, urinary antiseptics suchas nalidixic acid and antitubercular drugs such as isoniazid, andnon-steroid anti-inflammatory agents, such as phenylbutazones.

SUMMARY OF THE INVENTION It is therefore an important object of theinvention to provide a method for reducing normal peristaltic action soas to produce a condition of hypomotility and resultant enhanced drugabsorption by orally administering, simultaneously or sequentially, adrug substance. such as an antibiotic, and apolyoxypropylenepolyoxyethylene block polymer.

It is also an object of the invention to provide an improved method forenhancing the absorption of an antibiotic by administering anantibiotic, such as a tetracycline, griseofulvin and chloramphenicol,and a polyoxypropylene-polyoxyethylene block polymer.

It is a further object of the invention to provide a method fortreatment of animals, including humans, with tetracycline by orallyadministering a composition, preferably in capsule form, comprisingtetracycline and a polyoxypropylene-polyoxyethylene block polymer,wherein the combination of ingredients results in the enhancement of theabsorption of the tetracycline into the blood.

Further purposes and objects of this invention will appear as thespecification proceeds.

It has now been discovered that the foregoing objects may beaccomplished by orally administering to ani mals, either simultaneouslyor sequentially, about 5-90 percent by weight of a drug substance, suchas an antibiotic, and about 10-95 percent by weight of apolyoxypropylcue-polyoxyethylene block polymer having the formula:

ypropylene-polyoxyethylene block polymers have been found to depress oreliminate abnormal gas-' trointestinal motility. More specifically,these compositions have been found to be useful in the treatment of adisease entity: spasticity or hypermotility of the gastrointestinaltract. The reference, however, does not suggest that the polymer can beused to reduce normal peristaltic action to induce a transient conditionof hypomotility. These polymers (commercially available under thePluronics trademark from Wyandotte Chemical Company) have not been usedpreviously for enhancing drug blood levels by. increasing absorptionefficiency through the device of delaying transit of antibiotics andother drugs through the upper gastrointestinal tract.

Also, such polymers have been used with antibiotics, such astetracycline, for various purposes. Thus, in U.S. Pat. No. 3,l40,232,such polymers were used toimprove the color stability of a tetracyclineantibiotic. In U.S. Pat. No. 2,854,378, the polymer was used to make avaginal or rectal suppository which remains solid at temperatures belowC. None of the known prior art suggests the applicants method ofenhancing the drug level of orally administered drugs, particularlyantibiotics, by treatment with the foregoing method.

DESCRIPTION or THE PREFERRED EMBODIMENT Generally, our inventioncomprises a method for enhancing the dwell time of a drug in the upperpart of the gastrointestinal tract through the induction ofhypomotility. The method is carried out by orally administering,preferably in a capsule, a composition including a drug, such as anantibiotic, and about l-95 percent by weight of apolyoxypropylene-polyoxyethylene block polymer having the formula:

wherein b has a molecular weight of at least 900 and a and c represent amolecular weight of about to 80 percent of the total molecular weight ofthe polymer.

Although the description hereafter will relate generally toadministration of a composition comprising the drug and the blockpolymer in a conventional oral dosage form, such as in soft gelatincapsules, hard shell capsules and compressed tablets, it is to beunderstood that the drug and the polymer may be administered separatelyand sequentially. Thus, the polymer, in the proper amount, may beadministered first and the drug may, immediately thereafter, beadministered; or, alternatively the drug may be administered first andthe polymer immediately thereafter. Preferably, however, the treatmentis accomplished by simultaneously administering the polymer and the drugas a composition in a conventional oral dosage form.

Antibiotics having particularly advantageous results with ourmethodinclude tetracycline, griseofulvin and chloramphenicol. By theterm tetracyclines, we mean to include tetracycline,4-(dimethylamino)-l, 4, 4a, 5, 5a, 6, ll, l2a-octahydro-3, 6, l0, l2,l2a-pentahydroxy-6-methyl-l l l-dioxo-2-naphthacenecarboxamide, andderivatives of tetracycline including chlortetracycline,oxytetracycline, dimethylchlortetracycline, methacycline, anddoxycycline, all as bases, salts or hydrates. By the designationchloramphenicol we mean to include chloramphenicol, D(-)-threo-2,2-dichloro-N-[- ,8 hydroxy a (hydroxymethyl)-p-nitrophenethyl]acct-amide, and its esters including chloramphenicol palmitate,chloramphenicol pantothenate, chloramphenicol succinates and theirsodium salts.

By the term griseofulvin we mean to include macro and micro crystallinegriseofulvin, 7-chloro-2', 4, 6- trimethoxy-6'-methylspiro-[benzofuran-2( 3H l 2) cyclohexene1-3, 4'-dione.

In addition to the foregoing, other drugs amenable to enhancedabsorption as a result of delayed transit include corticosteriods,steroidal hormones, synthetic estrogens, thiazide diuretics, carbamatetranquilizers, phenothiazine tranquilizers, natural and syntheticantihypertensives, nitrate ester cardiac vasodilators, coumarin derivedanticoagulants, barbiturates, sulfa drugs, digitalis glyeosides,sulfonylurea hypoglycemic agents, urinary antiseptics such as nalidixicacid and antitubercular drugs such as isoniazide, and non-steroidantiinflammatory agents, such as phenylbutazones.

The aforesaid polymer acts as a non-anticholinergic, antispasmodic whichreduces normal motility or peristaltic action of the gastrointestinaltract so that the'antibiotic is more readily absorbed in the upper partof the gastrointestinal tract, namely, in the stomach and the upper partof the small intestine. The composition results in a delay in transit ofthe drug through the gastrointestinal tract. This increases dwell timeof the antibiotic in the upper part of the small intestine and in thestomach. Optimally, the polymer is present at about 30-90 percent byweight of the total weight of the polymer and antibiotic.

Advantageously, b of the aforementioned formula represents a molecularweight of about 950-4000 and the total of a and c represents a molecularweight of about 10-80 percent by weight of the total molecular weight ofthe polymer. Preferably b represents a molecular weight of about2,050-2,250 and a and 0 represent a molecular weight of about 30-50percent by weight of the total molecular weight of the polymer. Thesepolymers are non-ionic, surface active agents and are manufactured byWyandotte Chemical Company under the trademark Pluronics." ThePluronics' are available in liquid form and in solid form, includingflakes and powders. The detailed method of preparing the polymers isdescribed in US. Pat. No. 2,674,619. To be particularly effective, theblock polymer in each dosage unit should range from about 50 mg. to1,000 mg. Preferably, each dosage unit ranges from 250-500 mg. Thecomposition is preferably contained as a suspension in a filled softelastic gelatin capsule, in a granulation filled hard-shell capsule, orin a drug granulated compressed tablet in order to facilitate oraladministration. In the case of griseofulvin, an oral suspension may beprepared as well.

When the dosage of the drug substance or antibiotic is relatively high,as when tetracycline is the antibiotic in the composition, the lowerportion of the preferred range ofthe amount of polymer is used in orderto keep the size of the dosage form within relatively reasonable limits.In the case of an oral suspension, the higher portions of the range,that is, 750-l,000 mg. are used to advantage. The described compositionsare always administered orally.

The following examples more clearly disclose specific embodiments of theinvention.

Polyoxypropylene (MW. 2250) polyoxyethylene (40%) Semi-Liquid Polymer 5Propylene Glycol The drug (tetracycline HCl) is dispersed in thepolymers and propylene glycol and encapsulated in a soft gelatincapsule.

EXAMPLE ll Tetracycline HCl Dry-filled Hard Shell Capsules Ingredientsmgjcapsulc Tetracycline HCI 250 Polyoxypropylene (M.W. 2050) EXAMPLEll-Continued Tetracycline HCl Dry-filled Hard Shell Capsules lngredientsI mgJcapsule polyoxyethylene (70%) Solid Polymer 250 Sucrose powdered 75Starch 45 Cab-O-Sil l6 Stearic Acid 9 EXAMPLE 111 Tetracycline HCICompressed Tablets Ingredients mg./capsu1e Tetracycline HCl 250Pulyoxypropylcne (M.W. 2050) polyoxycthylcnc (70%) Solid Polymer 250Sucrose. powdered 75 Starch 45 (:tb-O-Sil l6 Ste-uric Acid 9 Agranulation is prepared as described in EXAMPLE I1 and compressed intotablets. These tablets may be either sugar-coated or film-coated. Thefilm-coated tablet is preferred.

EXAMPLE IV Chloramphenicol Soft Gelatin Capsules Ingredients mgjcapsuleChloramphenicol 2S0 Polyoxypropylene (M.W. 2750) polyoxyethylene (20%)Liquid Polymer 100 Polyoxypropylene (M.W. 1750) polyoxycthylene (10%)Liquid Polymer 170 Propylene Glycol 30 The drug is dispersed in thepolymers and propylene glycol and encapsulated in a soft gelatincapsule.

EXAMPLE V Griseofulvin Soft Gelatin Capsules Ingredients mgjcapsuleGriseofulvin 2 50 Polynxypropylene (M.W. I200) polyoxyethylene LiquidPolymer 500 Polyoxypropylene (M.W. 2250) polyoxyethylene (50%) SemiSolid Polymer 20 Propylene Glycol 30 The drug is dispersed in thepolymers and propylene glycol and encapsulated in a soft gelatincapsule.

EXAMPLE V1 The composition made in accordance with Example 1 wasadministered to dogs to determine the difference in the absorption ratesbetween capsules made in accordance with the invention and a commercialantibiotic (tetracycline HC] 250 mg., J. B. Roerig) not made inaccordance with the invention. It was found that after approximately 1/2 hours to 2 hours, the micrograms of tetracycline per milliliter ofblood serum dropped noticeably with the commercial antibiotic. The bloodlevel of the tetracycline in dogs treated with the composition made inaccordance with Example I remained relatively high. Up to 6 hours afterthe capsules were administered, the blood level for tetracyclineadministered in the composition of Example 1, when compared with thecontrol commercial dose, was substantially higher throughout the 6 hourobservation period. The data has shown an increase of 31 percent in theabsorption of the tetracycline in the blood over a 6 hour period ascompared to the commercial tetracycline capsule.

EXAMPLE V11 A cross-over serum level study with eight human sub jects(normal, healthy males) was undertaken employing soft elastic gelatincapsules made in accordance with Example 1 and a commercial antibiotic(tetracycline HC1250 mg, .1. B. Roerig) capsule as the control. Eachsubject received one 250 mg. capsule at least 1 hour after breakfast and1 week later received the alternate capsule. Blood samples werewithdrawn into sterile, -7 cc. Vacutainers" at 0, I, 2, 3, and 6 hoursafter the ingestion of the drug. The blood samples were stored inrefrigerator overnight. All samples from 1 days testing were assayed onthe following day at the same time.

At first, the blood samples were assayed by a fluorometric and amicrobiological method. The data indicated a linear correlation betweenthe two methods. Since the fluorometric assay is more accurate than themicrobiological method, the fluorometric procedure was used alone incompleting the study. The results are tabulated in Tables 1 and 11. Theblood level of tetracycline in human subjects treated with the softelastic gelatin capsule composition made in accordance with Example 1remained significantly higher'than the control. The data has shown anincrease of 29 percent in the absorption of the tetracycline in theblood over a 6 hour period as compared to the commercial tetracyclinecapsule.

On the average, the increase in absorption from the composition made inaccordance with Examine l is significant as compared to the absorptionfrom the control capsule (tetracycline HCI, 250 mg, .I. B. Roerig) asshown by this crossover study which takes into account individualvariations.

TABLEl Tetracycline HCl Serum Level 1n meg/m1. For A Cross-Over 6.1.Absorption Study In Eight Humans With Capsule Made As Example 1 HoursAfter Ingestion of Drug TABLE 11 Tetracycline HCl Serum Level In meg/ml.For

The drug is dispersed in the polymer and propylene glycol andencapsulated in a soft gelatin capsule.

EXAMPLE x11 A Cross-Over G.l. Absorption Study In Eight Humans wih Comm]Capsule (Te'mcyn) lngWdiEmSProP)lthioumcrl Soft Gelatin Cdpsulesmg y cpsule Hours After Ingestion of Drug propyhhioumcfl 50 sublecl 1 2 hr? 36 Polyoxypropylene (M.W. 1750) mcgJmls s/ polyoxyethylene (4117.) LiquidPolymer 190 3 0.96 1.43 1.77 1.42 The drug 1s d1spersed 1n the polymerand encapsug 3'2; Hg 3'3? lated in a soft gelatin capsule.

Average 0.66 1.17 1.24 0.38 Sulfadiazine Soft Gelatin Capsules StandardDeviation 10.13 :0.30 i012 $0.11 I gredients mg./capsule Sulfadiazine500 Polyoxypropylene (M.W 2050) EXAMPLE VIII polyoxyethylene (20%)Liquid Polymer 620 Propylene Glycol 60 Chlorothiazide Soft GelatinCapsules ln rcdients m ./ca sule g g p The drug 1s d1spersed 1n thepolymer and propylene Chlurothiuzide glycol and encapsulated in a softgelatin capsule. Polyoxypropylene (MW. 2050) 25 polyoxyethylene (20%)Liquid Polymer 270 EXAMPLE XIV Propylene Glycol 40 Polysorbate 80 3O YYP PW Z250) Sulfacetamide Soft Gelatin Capsules polyoxyethylene (50%)Semi-Solid Polymer 10 Ingredients mgJcapsule Sulfacetamide 500Polyoxypropylene (M.W. 1200) The drug dlspersed the polymersipolysorbate p polyoxyethylene (20%) Liquid Polymer I05 and propyleneglycol and encapsulated 1n a soft gelatin Polysorbate so 15 capsulePropylene Glycol 30 Polyethylene Glycol 400 400 EXAMPLE 1x salicylamidesoftcemin Capsules The ingredients in theformulation are m1xed well.ingredients mgJcapsule The resultmg suspension is encapsulated 1n a softgela- Salicylamide 30o capsule Polyoxypropylene (M.W. 2050)polyoxyethylene (20%) Liquid Polymer 235 40 EXAMPLE XV Polysorbate 80 25PmPyIene Glycol 40 Dienestrol Soft Gelatin Capsules Ingredientsmg./capsule Dienestrol 0.5 The drug 1s dispersed in the po1ymer,polysorbate 80 pnlynxypmpylcnc (MW 205") and propylene glycol andencapsulated 1n a soft gelatm pmynxyflhylcnc go Liquid Polymer 191mcapsule. Propylene Glycol 9.5

EXAMPLE X The drug, dienestrol, is dissolved in the polymer and IChlorpropamide f! Gelatin Capsules 50 propylene glycol and encapsulatedin a soft gelatin caplngredlcnts mg./capsule sule.

Chlorpropamide 100 Polyoxypropylene (M.W. 2050) EXAMPLE XVIpolyoxyethylene (20%) Liquid Polymer 325 Pwpylene Glycol 25Methyltestosterone Soft Gelatin Capsules lngredients mg./capsule Thedrug is dispersed in the polymer and propylene s y i M w 1750) oyoxypropy ene glycol and encapsulated 1n a soft gelatin capsule.olyoxyethylene (10%) Liquid Polymer 103 Polyoxypropylene (M.W. 22501EXAMPLE XI olyoxyethylene (50%) Semi-Liquid Polymer 87 PhenylbutazoneSoft Gelatin Capsules 'ngred'ems mgicapsu' The drug, methyltestosterone,is dispersed in the phenymumzone 100 polymers. The resulting suspensionis encapsulated in Polyoxypropylene (M.W. 2050) a ft gelatin capsule.polyoxycthylene (20%) Liquid Polymer 325 Propylene Glycol 2S EXAMPLE XV"Two normal healthy dogs of the Beagle strain that Ba S for X-rayPolyoxypropylene (M.W. 2050) Polyoxyethylene 20% Liquid Polymer Sp.Gravity 1.71

900 mg/ec Sample No. 3 had the following formulation:

Ba SO for X-ray 575 g Polysorbate 80 490 g Sp. Gravity 1.75 Ba S0 9 45mg/cc On the test day. one dog received 30 ml of Sample No. l, and theother dog received 30 ml of Sample No. 3. The test suspensions wereplaced directly into the stomach of each animal by stomach tube.

X-rays were taken of the gastrointestinal tract at zero hours(pre-dosing) and at )6, l, 1%, 2 and 4 hours past dosing.

One week later the study was repeated with each animal receiving theother suspension. X-rays were taken at the same time intervals asperformed initially.

In each case, Sample No. 3 left the stomach between A and l hour. Incontrast, Sample No. 1 did not leave the stomach after 4 hours.

EXAMPLE XVII] A cross-over serum level study with eight human subjects(normal, healthy males) was undertaken employing soft elastic gelatincapsules made in accordance with Example V and a commercial antifungal(Grisactin 250 mg., Ayerst) capsules as the control. Each subjectreceived one 250 mg. capsule at least one hour after breakfast and oneweek later received the alternate capsule. Blood samples were withdrawninto sterile, 7 cc Vacutainersat 0, 1, 2, 4, 6, 8. 12 and 24 hours afterthe ingestion of the drug. The blood samples were stored in refrigeratoruntil analysis. All samples from 1 days testing were assayed on thefollowing date at the same time. The 24 hour sample was analyzed on thesame day.

The blood samples were assayed by a modified. fluorometric procedure ofFischer and Riegelman [1. Pharm. Sci., 54, 1571 (1965)], which in turnis an adaptation of the method described by Bedford et al. [Nature, 184,364 (1959)]. The results are tabulated in Tables 111 and IV. The bloodlevel of griseofulvin in the human subjects treated with the softelasticgelatin capsule composition made in accordance with Example V remainedsignificantly higher than the control. The data has shown an increase of33 percent in the absorption of the griseofulvin in the blood over a 12hour period as compared to the commercial griseofulvin capsule.

The absolute standard deviations given in Tables 111 and 1V may seemhigh at first as the values range from 0.11 to 0.43 meg/m1. However,some typical data taken from the literature (S. Symchowicz and B.Katchen, J. Pharm. Sci., 57, 1383 (1968)], and listed in Table V showabsolute standard deviations range from 0.18 to 0.53 meg/m1. It can beseen that the standard deviations in Tables 11] and 1V fall in the rangeof those in Table V. A surprising observation is the similarity of thedata in Tables 1V and V. although the values in Table V are from 500 mg.doses of griseofulvin as compared to 250 mg. for the values in Table IV.

TABLE 111 Griseofulvin Serum Level in meg/ml. For A Crossover 6.].Absorption Study In Eight Humans with Control Capsule (Grisactin) HoursAfter lngestion of Drug 1 hr. 2 hr. 4 hr. 6 hr. 11 hr. 12 hr. 24 hr.Subject meg/ml. meg/ml. meg/n11. meg/m1. meg/ml. meg/m1. meg/m1.

Average 0.320 0.551 0.722 0.673 0.644 0.584 0.517

Std. Deviation 10.247 10.108 10.271 10.230 10.226 10.262 10.184

TABLE IV Griseofulvin Serum Level 1n mcg./ml. For A Cross-Over 6.1.Absorption Study In Eight Humans With Capsule Made In Accordance WithExample V Hours After Ingestion of Drug 1 hr. 2 hr. 4 hr. 6 hr. 8 hr. 12hr. 24 hr. Subject meg/ml. meg/m1. meg/m1. meg/m1. meg/m1. meg/m1.meg/m1.

TABLE lV C n tinued Griseot'ulvin Serum Level ln meg/ml. For ACross-Over 0.]. Absorption Study In Eight Humans With Capsule Made InAccordance With Example V Hours After Ingestion of Drug 1 hr. 2 hr. 4hr. 6 hr. 8 hr. 12 hr. 24 hr. Subject meg/ml. meg/ml. meg/ml. meg/ml.meg/ml. meg/ml. meg/ml.

7 0.000 0.110 [.024 0.875 0.855 0.671 0.571 8 0.185 0.602 0.908 0.7980.805 0.607 0.453 Average 0.306 0.620 0.941 0.924 0.9l7 0.721 0.582

Std. Deviation i0.27l $0.429 i0.25l 10.240 10.188 30.161 10.126

TABLE v TABLE v1 Data Obtained From Symchowicz and Katchen For ACross-Over Chloramphenicol Serum Level ln meg/ml For A Cross-Over SerumLevel Study In Eight Normal Humans Following The Oral G.l. AbsorptionStudy in Eight Humans With Administration Of 500 mg. Of GriseofulvinTablet Test Capsule (250 mg./capsule) Hours After Ingestion of DrugHours After Ingestion of Drug 2 hr. 4 hr. 8 hr. 25 hr. 1 hr. 2 hr. 4 hr.6 hr. 8 hr. Subject meg/m1. meg/ml. meg/ml. meg/ml. Sub ect meg/ml.meg/mlv meg/ml. meg/ml. meg/ml.

l 0.72 0.82 0.64 0.78 l 4.4 4.2 1.9 1.1 0.9 2 1.07 1.08 0.94 0.62 2 4.73.1 2.3 1.7 1.3 3 0.29 1.62 2.20 0.58 3 0.4 4.9 2.8 2.1 1.8 4 0.82 1.130.58 0.85 4 3.3 4.4 3.5 2.8 2.2 5 0.43 0.59 0.60 0.65 5 4.5 3.6 1.9 1.10.8 6 1.49 1.58 0.86 0.59 6 6.3 4.2 2.0 3.2 1.7 7 0.29 0.53 0.77 1.00 72.5 3.8 3.4 2.7 1.8 8 Average 3.7 4.0 2.5 2.1 1.7 Average 0.73 1.02 0.920.76 Std. Std. Deviation 10.41 10.41 0.53 $0.18 Deviation 11.9 10.6 :07:08 1'06 EXAMPLE x1x into sterile, 7 cc. Vacutainers at O, 1, 2, 4, 6and 8 40 hours after the ingestion of the drug; The blood samples werestored in refrigerator until analysis. All samples from one days testingwere assayed on the following day at the same time.

The blood samples were assayed by a modified pro- 4 cedure described byGlazko [A. J. Glazko, G. L. Hobby, editor: Antimicrobial Agents andChemotherapy 1966, Ann Arbor 1967, Am. Soc. of Microbiology, pp.655-665.] The results are tabulated in Tables V1 and VII. The bloodlevel of chloramphenicol in the human subjects treated with the softelastic gelatin capsule composition made in accordance with Example lVremained significantly higher than the control. The data has shown anincrease of 17.4 percent in the absorption of chloramphenicol in theblood over an 8 hour period as compared to the commercialchloramphenicol capsule.

Table VI contains data for seven human subjects because one personwithdrew from the test just before the final cross-over was completed.The absolute standard deviations given in Table VI are comparable tothose in Table VI]. In general, the standard deviations are high, thusthere are considerable individual variations in absorption. However, the17.4 percent increase in absorption from the composition made inaccordance with Example IV is significant as compared to the absorptionfrom the control capsule (Chloromycetin, 250 mg. Parke-Davis) becausethis cross-over study takes into account individual variations.

' One subject withdrew from test hcfun: final cross-over as completed.

TABLE Vll Chloramphenicol Serum Level ln meg/ml. For A Cross-Over G.l.Absorption Study In Eight Humans With Control Capsule (Chloromycetin,Parke-Davis 250' mg/capsule) Hours After Ingestion of Drug 1 hr. 2 hr. 4hr. 6 hr. 8 hr. Subject meg/ml. meg/ml. eg/ml. meg/ml. meg/ml.

Average 3.2 3.5 2.5 1.8 1.2

Std. Deviation $1.5 $1.0 $1.0 $0.8 $0.6

EXAMPLE XX A cross-over serum level study with 4 human subjects (normal,healthy males) was undertaken employing soft elastic gelatin capsulesmade in accordance with Example XI and a commercial, nonsteroid,antiinflammatory agent (Butazolidin, mg/tablet, Geigy) tablet as thecontrol. Each subject received one 100 mg. capsule or tablet at least 1hour after breakfast and 2 weeks later received the alternate dose.Blood samples were withdrawn into sterile 7 cc. Vacutaim ers" at 0, 1,2, 4, 8 and 24 hours after the ingestion of the drug. The blood sampleswere stored in refrigerator until analysis. All samples from one daystesting were assayed on the following day at the same time. The 24 hoursample was analyzed on the same day.

The blood samples were assayed by a modified method, described by Burnset al. [1. Pharmacol, Exp.

Ther., 109, 346 (I953)1r The results are tabulated in Tables VIII andIX. The blood level of phenylbutazone in the human subjects treated withthe soft elastic gelatin capsule composition made in accordance withExample XI remained-significantlyhigher than the control. The datareflects an increase of 186 percent in the absorption of phenylbutazonein the blood over an 8 hour period as compared to the commercialphenylbutazone tablet.

At first, the 186 percent seemed like a remarkable increase inabsorption. However, this increment correlates well with data from invitro dissolution studies. The in vitro dissolution rates indicated thetest capsule released the phenylbutazone quickly and completely. TheButazolidin tablet released phenylbutazone diminishingly slow, theresulting concentration is not conducive to absorption into the body asshown by the low level in the blood serum. The test capsule apparentlyfacilitated the absorption process by the quick release and the increasein the dwell time of the drug in the upper portion of thegastrointestinal tract where absorption takes place mainly.

TABLE VIII Phenylbutazone Serum Level In meg/ml. For A Cross-Over (3.1.Absorption Study In Four Humans With Test Capsule (100 mgJcapsule) HoursAfter Ingestion of Drug lhr. 2 hr. 4 hr. 8 hr. 24 hr.

Phenylbutazone Serum Level 1n meg/ml. For A Cross-Over GastrointestinalAbsorption Study In Four Humans With Control Tablet (Butazolidin. 100mgltablet.

Geigy) Hours After Ingestion of Drug 1 hr. 2 hr. 4 hr.v 8 hr. 24 hr.Subject meg/ml. meg/ml. meg/ml. meg/ml. meg/m1.

Average 1) 6 2.0 5.6 7.8 6.9

Stdv Deviation 31.2 3.2.5 $1.) :1 7 3:1 2

EXAMPLE XXI A cross-over blood serum level experiment with four humansubjects (normal, healthy males) was undertaken using soft elasticgelatin capsules and a commercial, non-steroid, anti-inflammatory agenttablet (Butazolidin, 100 mgjtablet, Geigy) as the control. The softelastic gelatin test capsule was made by encapsulating a suspension of100 mg phenylbutazone in 100 mg. of polysorbate 80 along with 90 mg. PEG400 per capsule.

6 Each human sub ect received one capsule or tablet at least one hourafter breakfast and two weeks later received the alternate dose. Bloodsamples were withdrawn into sterile, 7 cc. Vacutainers at 0,1. 2, 4, 8,.and 24 hours after the ingestion of the drug. The blood test capsuleremained higher than the control tablet.

The data indicated however, that the absorption of phenylbutazone fromthe polysorbate base was percent greater than the control tablets.Referring to Example XX, the enhanced absorption of phenylbutazone madewith the polyoxypropylene polyoxyethylene block polymers represented a186 percent increase as compared to the same control tablets.

The data indicate that the control tablet is a poor dosage form and thatthe absorption of phenylbutazone cannot be affected positively by themere use of an efficient surface-active agent. In addition, the datademonstrate that the delayed transit provided by the polyoxypropylenepolyoxyethylenc block polymers is a real phenomenon and is not dependenton surface activity alone.

TABLE x Phenylbutazone Scrum Level In meg/m1. For A Cross-OverGastrointestinal Absorption Study In Four Humans With Test Capsule 1 100mglCapsule) Hours After Ingestion o1 Drug Phenylbutazone Serum Level Inmcg/ml. For A Cross-Over Gastrointestinal Absorption Study In FourHumans With Control Tablet (Butazolidin. I00 mgltablet. Geigy) HoursAfter Ingestion of Drug I hr. 2 hr. 4 hr. 8 hr. 24 hr. Subject meg/ml.meg/ml. meg/ml. meg/ml. meg/ml.

Average 1.4 5.2 8.3 7.6 6.3

Std. Deviation i0) $2.4 $2.8 ill) $2.0

EXAMPLE xxn A cross-over blood serum level experiment with four humansubjects (normal, healthy males) was undertaken employing soft elasticgelatin capsules and a commercial antibiotic capsule (Tetracyn, 250mg/capsule, Roerig) as the control. A soft elastic gelatin test capsulewas made by encapsulating a suspension of 250 mg. tetracycline HCl in300 mg. Polysorbate 80 per capsule. Each human subject received one 250mg. capsule at least one hour after breakfast and one week laterreceived the alternate capsule. Blood samples were withdrawn intosterile, 7 cc Vacutainers at 0, l, 2, 3 and 6 hours after the ingestionof the drug. The blood samples were stored in refrigerator untilanalysis. All samples from I days testing were assayed on the followingday at the same time.

The blood samples were assayed by a fluorometric procedure as reportedby Kohn [Anal. Chem., 33, 862 (1961)]. The results are tabulated inTables X11 and Xlll. The blood level of tetracycline HCl in the humansubjects treated with the soft elastic gelatin test capsule remainedsignificantly lower than the control. The data indicated that theabsorption of tetracycline l-lCl from polysorbate 80 was 73 percent ofthat of the control capsules.

The results of the present study show that the presence of a surfactantin a formulation is no assurance of better drug absorption. Further, itdemonstrates that the delayed gastrointestinal transport realized withthe polyoxypropylene-polyoxyethylene block polymer base capsules isresponsible for the enhanced absorption rather than mere surfaceactivity.

TABLE Xll Tetracycline HCl Serum Level in meg/ml For A Cross-Over G.l.Absorption Study In Four Humans With Test Capsule (250 mg/capsule withPolysorbate 80) Tetracycline HCl Serum Level in meg/ml For A Cross-OverG. l. Absorption Study In Four Humans With Control Capsule (Tetracyn,250 mg/capsule, Roerig) Hours After Ingestion of Drug l hr. 2 hr. 3 hr.6 hr. Sub ect meg/ml. meg/ml. mcg/ml. meg/ml.

3 [.55 2.l2 2.26 l.4l

Average l.l L40 L57 L14 Std. Deviation $0.71 $0.86 $0.58 $0.65

EXAMPLE XXlll A cross-over serum level study with eight human subjects(normal, healthy males) was undertaken employing tablets made inaccordance with the following formulation:

GRISEOFULVIN COMPRESSED TABLETS, ET-l Ingredients mgjtablet Griseofulvin250 Polyoxypropylene (M.W. 2050) polyoxyethylene Solid Polymer 250Sucrose, Powder Starch 60 Cab-O-Sil 20 Solka Floc Stearic Acid 9 Theblood samples were assayed by a modified fluorometric proceduredescribed by Fischer and Riegelman [.I. Pharm. Sci., 54, 1571 (1965)}.Results are tabulated in Tables XIV and XV. The blood levels ofgriseofulvin in the human subjects treated with the tablets containingan equal weight of the polyoxypropylene polyoxyethylene solid polymerwere significantly higher than the control. There was an increase of 57percent in the absorption of griseofulvin in the blood over a twelvehour period as compared to the commercial griseofulvin capsule.

The results from the present study further show that the presence of thepolyoxypropylene polyoxyethylene block polymer in a pharmaceuticalformulation significantly increases the blood level of the activeingredient. Although the test tablet contains only 250 mg. griseofulvinit gave rise to a blood level higher than that from a 500 mg. tablet asreported by Symchowicz and Katchen [.l. Pharm. Sci., 57, 1383 (1968)],as listed in Table V. For example, after four hours, the test tabletelicited a blood level of l.22 meg/ml. as compared to 1.02 meg/ml. fromthe 500 mg. tablet. The test tablet gave even a higher blood level thanthe capsule made in accordance with Example V. The difference betweenthe liquid polymer used in the Example V capsule and the solid polymerin the test tablet is the higher content of the polyoxyethylene moietyin the latter polymer.

Griseofulvin Serum Level In meg/m1. For A Cross-ver G.I. AbsorptionStudy In Eight Humans With Test Tablet Hours After Ingestion of Drug 1hr. 2 hr. 4 hr. 6 hr. 8 hr. 12 hr. 24 hr. Sub ect meg/ml. meg/ml.meg/ml. meg/ml. meg/m1. meg/ml. meg/ml.

Average 0.78 1.25 1.19 1.14 1.17 0.92 0.311

Std. Deviation 10.75 $0.47 10.48 i048 10.63 10.49 1033 TABLE XVGriseofulvin Serum Level 1n meg/ml. For A Cross-Over G.I. AbsorptionStudy In Eight Humans With Control Capsule (Grisactin) Hours AfterIngestion of Drug 1 hr. 2 hr. 4 hr. 6 hr. 8 hr. 12 hr. 24 hr. Subjectmeg/m1. meg/ml. meg/ml. mcg/ml. meg/ml. meg/ml. meg/m1.

Average 0.55 0.82 0.80 0.71 0.71 0.59 0.46 Std. Deviation 0.43 0.47$0.40 $0.28 $0.27 10.21 10.12

EXAMPLE XXIV A cross-over study has been undertaken with two differentsets of four normal, healthy, human male subjects. The gastrointestinalabsorption, blood serum level and urinary excretion of salicylamide weredetermined following the oral ingestion of the test capsule and acommercial tablet as the control. The test capsule was made inaccordance with Example IX but without the use of polysorbate 80 andpropylene glycol. The commercial tablet contained 5 grains ofsalicylamide. The results shown below have been normalized to a 300 mg.dose of salicylamide. Each human subject received one capsule or tabletat least 1 hour after breakfast and one week later received thealternate dose. Blood samples were withdrawn into sterile, cc. ccvacutuincrs at 0, l. 2. 3 and 6 hours after the inges tion 01 the drug.The blood samples were stored in a refrigerator until analysis. Theurine samples were collected into bottles at 0, I, 2, 3, 4, 5, and 7hours. Each urine sample's volume was recorded, then the urine wasstored in a refrigerator until analysis. All samples from I days testingwere assayed on the following dayat the same time. The method publishedin J. Pharm. Sci., 60, 1092 (1971) was used for the determination ofsalicylamide in the blood and urine samples. Results The blood serumdata are shown in Tables XVI and XVII. The blood level results show a 9percent increase in absorption of salicylamide from the soft gelatintest capsule as compared to the control tablet. The urine data aretabulated in Tables XVIII and XIX. The urinary excretion rate ofsalicylamide results in a 12 percent increase from the soft gelatin testcapsule as compared to the tablet control. The average recovery ofsalicylamide over the first seven hours was 85.1 percent of the dosefrom the tablet control. The higher first and second hour salicylamideserum levels achieved with the test capsule reflects early and promptanalgesic response.

TABLE XIV salicylamide Serum Level In meg/nil. For A Cross-Over 0.1.Absorption Study In Four l-lumans with Test Capsule (300 mgJcapsule)I-Iours After Ingestion of Drug Salicylamide Serum Level 1n meg/m1. ForA Cross-Over G.l. Absorption Study In Four Humans With Control Tablet 15grains. normalized to 300 mg/tablet) Hours After Ingestion of Drug 1 hr.2 hr. 3 hr. 6 hr. Subject meg/m1. meg/ml. meg/m1. meg/ml.

Average 5.89 5.94 2.85 0.53 Std. Deviation $2.21 $2.54 $0.69 10.30

TABLE XVIII Salicylamide Urinary Excretion Rate in mg/hr. For A Cross-Over G. 1. Absorption Study in Four Humans With Test Capsule (300mg/capsule) Hours After Ingestion of Drug 1 hr. 2 hr. 3 hr. 4 hr. 5 hr.7 hr. Subject mg/hr. mg/hr. mg/hr. mg/hr. mg/hr. mg/hr.

I 16.9 67.8 88.7 50.6 27.3 7.5 2 19.1 71.8 80.6 50.1 28.2 8.4 3 32.987.3 95.0 28.5 11.4 4.9 4 94.2 97.6 37.3 13.9 7.7 5.1 Average 40.8 81.175.4 35.8 18.7 6.5 Std. Deviation $36.2 $13.8 $26.0 i178 :10.8 11.7

TABLE XIX Salicylamide Urinary Excretion Rate In mg/hr. For A Cross-Over 6.1. Absorption Study In Four Humans With Control Tablet (5 grains,normalized to 300 mg/tablet) Hours After Ingestion of Drug 1 hr. 2 hr. 3hr. 4 hr. 5 hr. 7 hr. Subject mg/hr. mg/hr. mg/hr. mg/hr. mg/hr. mg/hr.

l 9.6 72.0 59.9 31.1 14.1 17.6 2 0.0 19.0 83.6 76.4 43.4 18.5 3 111.891.0 23.1 10.0 5.9 3.8 4 35.5 96.0 56.4 32.3 21.5 8.1 Average 39.2 69.555.8 37.5 21.2 12.0 Std. Deviation 250.6 235.2 3124.8 $27.9 $15.9 $7.2

EXAMPLE XXVI Prepared soft gelatin capsules contained 325 mg. ofsalicylamide and 250 mg. of one of the three test vehicles (PEG 400,Carbowax 6,000 and poloxamers). Four normal human males were used forthe present study in a three by four Latin Square Design experiment.Each subject ingested the designated capsule in the morning on a fastedstomach along with 250 ml. of tap water. Urine samples were collected at0, l, 2, 3, 4, and 6 hours after the oral ingestion of the capsule.After recording the volumes, the urine samples were stored in arefrigerator pending analysis. The urine samples were determined forsalicylamide content by the published method which appeared in J. Pharm.Sci., 60, 1092-1095 (1971).

RESULTS AND CONCLUSIONS The individual data, their averages and standarddeviations are tabulated in Table XX for the three vehicles. Thestandard deviations are about normal for this type of data. The averageresults .were plotted. Both vehicles PEG 400 and Carbowax 6,000 appearedto have slightly faster rate at the 2 hour mark. However, the poloxamershave a more prolonged effect. This extent effect was best shown bycomparing the relative area under curves and expressing them as relativepercentages. The results are as follows; setting Carbowax 6,000 as 100:

Vehicle Relative "/1 ('nrlnm'ax 6000 PH; 400 1. 94 Inluxumer 234 inPoloxamer 212 65 crease in solubility may explain the slight increase ininitial rate. However, the increase in the extent of excretion by thepoloxamers may be attributed to the hypomotility effect on the GI tractinduced by the poloxamers.

TABLE XX Urinary Excretion Rate of Salicylamide After the Ingestion of325 mg. Of The Drug Formulated In 250 mg. Of the Various Vehicles A.Polyethylene glycol 400 Salicylamide, mg/hr.

Subject 1 hr. 2 hr. 3 hr. 4 hr. 6 hr.

H 49.8 118.3 61.7 33.7 9.3 M 36.2 124.1 66.0 32.4 12.1 F 84.0 111.7 43.622.5 4.6 V 35.3 94.0 60.3 31.7 15 Average 51.3 112.0 57.9 30.1 10.4

Std. Deviation 122.8 i $9.8 $5.1 14.7

B. Carbowax 6000 Salicylamide. mg/hr.

Subject 1 hr. 2 hr. 3 hr. 4 hr 6 hr.

V 58.6 116.3 52.8 28.2 100 H 96.7 92.3 32.6 23.3 13.1 M 37.2 63.3 38.241.5 25.1 V 18.1 107.9 80.8 41.1 16.3 Average 52.7 95.0 51.1 33.5 16.1

Std. Deviation 133.7 $23.3 221.6 19.4. 1:6.5

C. 15% Poluxamer 234 in Poluxamcr 212 Salicylamide. mg/hr Subject I hr.2 hr. 3 hr. 4 hr. 6 hr.

F 19.0 105.9 91.5 36.7 9.0 H 20.2 139.6 102.9 33.6 9.4 M 8.6 62.2 69.0119.2 32.3 V 19.9 69.5 108.3 55.6 13.8 Average 16.9 94.3 92.9 61.3 16.1

Std. Deviation $5.6 235.7 117.4 239.8 :11.0

EXAMPLE XXVII A test was conducted to compare the gastrointestinaltransit time of a Pluronic and other surfactants, by X-ray study, usingfasted Beagle dogs as test animals.

' The test composition (NO.l) was:

Barium sulfate for x-ray 52.66 Poloxamer 212 47.34

Sp. gr. 1.71

A 30 cc. dose contains 24.3 grams of Poloxamer 212. The composition(N02) with surfactants was:

A 30 cc. dose contains 8.0 grams of carbowax 6000 and 16.0 grams of PEG400 Seven normal, healthy dogs of the Beagle strain that had beenacclimated to the laboratory environment were used in this experiment.

The animals had been deparasitized and vaccinated and consumed theirdaily ration of Purina Chow supplemented by water ad libitum.

The animals were fasted for eighteen hours prior to closing. On the dayof the experiment sample No. 2 was diluted one part plus one part(v/v)with distilled water since its original consistency could not beadministered orally.

Two of the test animals were dosed with 30 ml. of sample No. l and twowere dosed with 60 ml. of the 1:1 dilution of sample No. 2. The testsuspensions were placcd directly into the stomach of each animal bymeans of a stomach tube.

X-rays were taken of the gastro-intcstinal tract at hours (pro-dosing)and at k, 1, l k, 2 A, and 3 b hours post dosing.

One week later, the study was repeated with each surviving animalreceiving the other suspension. X-rays were taken at the same timeintervals as reported initially. A Westinghouse machine, Model No. 3065,was used to take the X-rays. Four hours post dosing each animal receivedits regular ration of Purina Chow.

dosing. Dead at 3% hours post -.Continued Dosing Schedule Dog No.Initial X-Over dosing. 57.1 No. l Slight visualization in smallintestine l hour post dosing. 578 No. 1 Animal vomited 9% hour postdosing. 572 No. 2 Sample visible in small intestine at 1% hours postdosing. 576 No. 2 Sample highly visible in small intestine at 55 hourpost dosing. 573 No. 2 Some visualization in small intestine at 1 hourpost dosing. 574 No. 2 Sample highly visible in small intestine at khour post dosing. 571 No. 2 Sample highly visible in small intestine atA hour post dosing. 573 No. 1 Animal vomited 1% hours post dosing. 574No. l Animal vomited 1% hours post dosing Each of the animals which werefed barium sulfate in the poloxamer 212 base received 3.04 gram ofpoloxamer 212 per kilo gram of body weight. This dose level is greaterthan the LD value determined for polox amer 212, which is 2.83 gram perkilogram for both rats and beagle dogs. This is considered the reasonwhy one of the five dogs receiving the poloxamer 212 composition died.The LD test is not precise. The 2.83 gram per kilogram figure representsthe mean LD The statistical projection, based on the data accumulated inarriving at this mean, indicates that the LD will range from 2.15 gramper kilogram to 3.75 gram per kilogram. H

The results or responses as indicated in the report show two trends, Asthe dogs dosed with the test'composition No. l, the barium sulfateremained in the stomach for 3 a hours, the length of the experiment.With the dogs dosed with the other composition, No. 2, the bariumsulfate appeared in the small intestine from h to l 1% hours afterdosing.

EXAMPLE-XXVlll Twenty-seven gm of X-ray grade barium sulfate wasmechanically suspended in 340ml. of distilled water. Each of four dogsreceived this type of suspension. X rays were taken at 0 hours and at0.5, l, 2, 3, and 4 hours after feeding the suspension to .each dog. DogNo. 581 weighed 10.34 kilograms, Dog No. 585 weighed 7.18 kilograms, DogNo. 586 weighed 11.81 kilograms, and Dog No. 587 weighed 9.43 kilograms.In each case, the barium sulfate had moved into the intestinal tract bythe first 0.5 hour of absorption- These data serve as a control orcomparison for the data of Examples XVII and XXVll.

While in the foregoing, there has been provided a detailed descriptionof particular embodiments of the present invention, it is to beunderstood that all equivalents obvious to those having skill in the artare to be included within the scope of the invention as claimed. What weclaim and desire to secure by Letters Patent l. A method for enhancinggastrointestinal absorption of a drug of the type which ispreferentially absorbed in the upper part of the gastrointestinal tract,said drug also being capable of having the amount of absorption extendedby having the dwell time of said 23 drug in the upper part of thegastrointestinal tract ex tended by prior induction of hypomotility,said method comprising the steps of sequentially absorbing in the upperpart of the gastrointestinal tract an effective oral unit dosage amountof said drug, after first commencing absorbing in the upper part of thegastrointestinal tract about 30-95 percent by weight of a material, saidpercentage being relative to the total weight of said drug and saidmaterial, said material being a polyoxypropylene polyoxyethylene blockpolymer having the formula:

24 hypomotility enhancing the desired gastrointestinal absorption ofsaid drug, said polymer being the essential gastrointestinal absorptionenhancing agent.

2. The method of claim 1 wherein b of said polymer represents amolecular weight of 950-4,000 and a and c represent a molecular weightof 10-80 percent by weight of the total molecular weight of saidpolymer.

3. The method of claim 1 wherein b of said polymer represents amolecular weight of 2,050-2,250 and a and c represent a molecular weightof about 30-50 percent by weight of the total molecular weight of saidpolymer.

4. The method of claim 1 wherein the said block polymer is about 30-90percent by total weight of said drug and said material.

5. The method of claim 1 wherein said block polymer is about 50 percentof the total weight of said drug and said material.

6. The method of claim 1 wherein said sequential upper gastrointestinaltract hypomotllity inducing and drug absorbing steps overlap or aresimultaneous by presentation in the upper gastrointestinal tract in thesame soft gelatin capsule.

1. A METHOD FOR ENHANCING GASTROINTESTINAL ABSROPTION OF A DRUG OF THETYPE WHICH IS PREFERENTIALLY ABSORBED IN THE UPPER PART OF THEGASTROINTESTINAL TRACT, SAID DRUG ALSO BEING CAPABLE OF HAVING THEAMOUNT OF ABSORPTION EXTENDED BY HAVING THE DWELL TIME OF SAID DRUG INTHE UPPER PART OF THE GASTROINTESTINAL TRACT EXTENDED BY PRIOR INDUCTIONOF HYPOMOTILITY, SAID METHOD COMPRISING THE STEPS OF SEQUENTIALLYABSORRBING IN THE UPPER PART OF THE GASTROINSTESTINAL TRACK ABOUT 3-95PERCENT BY AMOUNT OF SAID DRUGH, AFTER FIRST COMMENCING ABSORBING IN THEUPPER PART OF THE GASTROINTESTINAL TRACK ABOUT 30-95 PERCENT BY WEIGHTOF A MATERIAL, SAID PERCENTAGE BEING RELATIVE TO THE TOTAL WEIGHT OFSAID DRUG AND SAID MATERIAL, SAID MATERIAL BEING A POLYOXYPROPYLENEPOLYOXYETHYLENE BLOCK POLYMER HAVING THE FORMULA:
 2. The method of claim1 wherein b of said polymer represents a molecular weight of 950-4,000and a and c represent a molecular weight of 10-80 percent by weight ofthe total molecular weight of said polymer.
 3. The method of claim 1wherein b of said polymer represents a molecular weight of 2,050-2,250and a and c represent a molecular weight of about 30-50 percent byweight of the total molecular weight of said polymer.
 4. The method ofclaim 1 wherein the said block polymer is about 30-90 percent by totalweight of said drug and said material.
 5. The method of claim 1 whereinsaid block polymer is about 50 percent of the total weight of said drugand said material.
 6. The metHod of claim 1 wherein said sequentialupper gastrointestinal tract hypomotility inducing and drug absorbingsteps overlap or are simultaneous by presentation in the uppergastrointestinal tract in the same soft gelatin capsule.